In this proposal, we focus on understanding the interactions between the HIV-1 envelope glycoproteins and the newly discovered second receptors that function during the fusion of HIV-1 with CD4+ cells. The recent findings from ourselves and others that the _-chemokine receptor CKR-5 is involved in HIV-1 entry, and that _-chemokines antagonize this process, open up an entirely new area of research. There are implications for drug development, for pathogenesis and transmission, for the humoral immune response to HIV-1, and for non-human primate models important to vaccine development. To exploit these discoveries fully requires knowledge of the ways in which the second receptors function in virus entry, and of which second receptors are used by different HIV-1 strains and different non-human primate immunodeficiency viruses. Our first specific aim is to characterize the interactions between HIV-1 gp120 and second receptors, notably CKR-5, and to develop antagonists of this process. In our second specific aim, we will clone and characterize the second receptors for primate immunodeficiency viruses, and for HIV-2, from human, macaque, mangabey and chimpanzee cells. As our third specific aim, we will determine whether HIV-1 strains from different genetic subtypes differ in their abilities to use different second receptors. Our fourth specific aim is to understand how cell-specific variables in second receptor expression impact on HIV-1 entry and its sensitivity to _-chemokines. To achieve these goals, a collaboration has been established between the Moore and Marx laboratories at the Aaron Diamond AIDS Research Center, Progenics Pharmaceuticals, Inc. (Paul Maddon) and the Sakmar Laboratory at the Rockefeller University. These groups possess different, but complementary, skills that will enable the goals of this proposal to be efficiently fulfilled. FUNDING NIH (R01 AI41420) PUBLICATIONS Chen Z., D. Kwon, Z. Jin, S. Monard, P. Telfer, M.S. Jones, R. Aguilar, D.D. Ho, and P.A. Marx. Natural infection of a homozygous 24 CCR5 red-capped mangabey with a 2b-tropc SIV. Journal of Experimental Medicine, 199:2057-2065, 1998. Chen, Z., A. Gettie, D.D. Ho and P.A. Marx. Primary SIVsm isolates use the CCR5 co-receptor from sooty mangabeys naturally infected in West Africa a comparison of coreceptor usage of primary SIVsm, HIV-2 and SIVmac. Virology, 246:113-124, 1998. Palacios, E., L. Digilio, H.M. McClure, Z. Chen, P.A. Marx, M.A. Goldsmith and R.M. Grant. Parallel evolution of CCR5-null phenotypes in humans and in a natural host of simian immunodeficiency virus. Current Biology, 8:943-946, 1998. Marx, P.A. and Z. Chen. The function of simian chemokine co-receptors in the replication of SIV. In Seminars of Immunology. 10:215-223, 1998. Mo, H., S. Monard, H. Pollack, J. Ip, G. Rochford, L. Wu, J. Hoxie, W. Borkowsky, D.D. Ho and J.P. Moore. Expression patterns of the HIV type 1 coreceptors CCR5 and CXCR4 on CD4+ T cells and monocytes from cord and adult blood. AIDS Research and Human Retroviruses, 14:607-617, 1998. Zhang, Y-J., T. Dragic, Y. Cao, L. Kostrikis, D.S. Kwon, D.R. Littman, V.N. KewalRamani and J.P. Moore. Use of co-receptors other than CCR5 by non-syncytium-inducing adult and pediatric isolates of human immunodeficiency virus type is rare in vivo. Journal of Virology, 72:9337-9344, 1998.